All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Laurie E Harrington

Lalita Shevde-Samant

Christopher A Klug

Donald J Buchsbaum

Eddy Yang

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


ST6Gal-I adds α2-6 sialic acids to select N-glycosylated cell surface receptors, thereby modulating receptor function and intracellular signaling. ST6Gal-I is upregulated in various carcinomas and confers cancer stem cell (CSC) properties evidenced by tumorspheroid growth, chemoresistance and tumor initiating potential. In pancreatic ductal adenocarcinoma (PDAC), ST6Gal-I conferred gemcitabine resistance by abrogating DNA damage and altering expression levels of gemcitabine metabolism genes. Further, ST6Gal-I promoted resistance to chronic gemcitabine treatment. Additionally, metastatic clones of a PDAC cell line had increased ST6Gal-I expression and ST6Gal-I knockdown enhanced gemcitabine sensitivity. To investigate the physiological consequences of ST6Gal-I in PDAC, murine models were used. PDAC can be replicated in murine models utilizing pancreas specific oncogenic-K-Ras (KC). We generated ST6Gal-I knock-in mice with oncogenic-K-Ras (KSC), which presented with significantly decreased overall survival (median = 4.3 months) compared KC mice (median=14 months). This was coupled with a marked increase in distal metastasis in KSC mice, indicative of aggressive disease progression. ST6Gal-I expression was shown to mediate enhancement of acinar to ductal metaplasia (ADM), which is a process of dedifferentiation of acinar cells to more stem-like ductal cells. Pancreatic stem cell derived organoids from KC, KSC, SC (ST6Gal-I knock-in alone) and wild type (WT) mice were generated to investigate alterations in stem cell behavior. Compared to WT and KC, SC and KSC organoids had increased organoid growth and maintenance. Furthermore, knock-down of ST6Gal-I expression in KC organoids significantly hindered organoid growth. To interrogate the role of ST6Gal-I in dedifferentiation of acinar cells, the 266-6 acinar cell line was used. ST6Gal-I overexpression increased expression of ductal markers while knockdown enhanced expression of acinar markers. Furthermore, upon induction of pancreatitis, SC mice presented with increased ADM, compared to WT. Furthermore, RNA sequencing of WT and SC mice depicted an upregulation in key stem/developmental pathways, Wnt, Notch and Hedgehog. Importantly, acinar cells from KSC mice aberrantly upregulated the key ductal marker Sox9. With single cell RNA sequencing, we determined that acinar cells in KSC mice enhanced expression of ductal and stem cell genes when compared to KC mice. These collective studies implicate ST6Gal-I as a potent driver of PDAC pathogenesis.